Impaired wound healing is an important clinical problem in diabetes resulting in failure to completely heal diabetic foot ulcers and more that 75,000 lower extremity amputations annually. Based on our extensive clinical work we have pointed to the synergistic pathophysiology of neuropathy and ischemia in creating the compromised biology of the diabetic foot. In this proposal we plan to expand our studies and further evaluate the role on nerve dysfunction in new animal models of diabetic wound healing. The main hypothesis of the current proposal is that neuropeptides play an important role in wound healing and that the lack of them due to peripheral neuropathy, combined with the diabetes-related chronic inflammation, leads to impaired angiogenesis and wound healing. Our specific aims are: 1. To develop in vivo diabetic rabbit models for investigating cutaneous wound healing and failure to heal in the presence of multiple states: diabetes alone, diabetes with peripheral ischemia, diabetes with peripheral neuropathy, and diabetes with both peripheral ischemia and neuropathy, 2. To evaluate the wound healing progress, cytokine expression, angiogenesis and tissue oxygenation in substance P and substance P neurokinin-receptor (NK-1r), KO diabetic and non-diabetic mice. We will also evaluate the same parameters in wild type mice (diabetic and non diabetic) after combined peripheral administration of NK-1R, antagonist, and 3. To study the expression of neuropeptides at the skin level of neuropathic and non-neuropathic diabetic patients and compare it to healthy control subjects. We will also examine whether the neuropeptide expression is related to the development of foot ulceration and the failure to heal foot ulcers. These studies, from bench to bedside, will greatly advance knowledge in the broad area of wound healing and will specifically result in the development of basic and translational research data that can lead to the development of new therapeutic approaches to improve wound healing in diabetes